tbuckley/cabot-search huggingface dataset:
A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy
Authors: Qianhua Feng, Yutong Hao, Shuaiqi Yang, Xiaomin Yuan, Jing Chen, Yuying Mei, Lanlan Liu, Junbiao Chang, Zhenzhong Zhang, Lei Wang
Journal: Acta Pharmaceutica Sinica B (2022)

The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8
In This Issue
Journal: Arthritis & Rheumatology (2022)

Affects Disease Subsets in RAAnti-peptidylarginine deiminase 4 (anti-PAD4) antibodies can have different constant regions, suggesting that the antibodies are generated in distinct immune m i c r o e n v i r o n m e n t s .In this issue, Gómez-Bañuelos et al (p.1746) report the results of their exploration of the clinical associations of different isotypes and IgG subclasses of anti-PAD4 antibodies in rheumatoid arthritis (RA) patients.They found that anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE antibodies identify discrete disease subsets in RA.The investigators found that anti-PAD4 IgG1 was more predictive of radiographic progression than the most utilized serologic clinical indicators and was independent of treatment or RA duration.The results suggest that heavy chain usage drives distinct effector mechanisms of anti-PAD4 antibodies in RA.
Journal Club
Journal: Arthritis & Rheumatology (2022)

Affects Disease Subsets in RAAnti-peptidylarginine deiminase 4 (anti-PAD4) antibodies can have different constant regions, suggesting that the antibodies are generated in distinct immune m i c r o e n v i r o n m e n t s .In this issue, Gómez-Bañuelos et al (p.1746) report the results of their exploration of the clinical associations of different isotypes and IgG subclasses of anti-PAD4 antibodies in rheumatoid arthritis (RA) patients.They found that anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE antibodies identify discrete disease subsets in RA.The investigators found that anti-PAD4 IgG1 was more predictive of radiographic progression than the most utilized serologic clinical indicators and was independent of treatment or RA duration.The results suggest that heavy chain usage drives distinct effector mechanisms of anti-PAD4 antibodies in RA.
Effect of granulocyte colony-stimulating factor on toxicities after CAR T cell therapy for lymphoma and myeloma
Authors: Kevin Charles Miller, Patrick Connor Johnson, Jeremy S. Abramson, Jacob D. Soumerai, Andrew J. Yee, Andrew R. Branagan, Elizabeth K. O’Donnell, Anna Saucier, Caron A. Jacobson, Matthew J. Frigault, Noopur S. Raje
Journal: Blood Cancer Journal (2022)

Chimeric antigen receptor T cells (CAR T) are groundbreaking therapies but may cause significant toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias. Granulocyte colony-stimulating factor (G-CSF) is often used to mitigate neutropenia after CAR T, but there is no consensus recommended strategy due to hypothesized, but largely unknown risks of exacerbating toxicities. To investigate the impact of G-CSF, we retrospectively analyzed 197 patients treated with anti-CD19 CAR T for lymphoma and 47 patients treated with anti-BCMA CAR T for multiple myeloma. In lymphoma, 140 patients (71%) received prophylactic G-CSF before CAR T (mostly pegylated G-CSF) and were compared with 57 patients (29%) treated with G-CSF after CAR T or not exposed. Prophylactic G-CSF was associated with faster neutrophil recovery (3 vs. 4 days, P < 0.01) but did not reduce recurrent neutropenia later. Prophylactic G-CSF was associated with increased grade ≥2 CRS (HR 2.15, 95% CI 1.11-4.18, P = 0.02), but not ICANS. In multiple myeloma, prophylactic G-CSF was not used; patients were stratified by early G-CSF exposure (≤2 days vs. ≥3 days after CAR T or no exposure), with no significant difference in toxicities. Future trials should clarify the optimal G-CSF strategy to improve outcomes after CAR T.
Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia
Authors: Patrizio Panelli, Elisabetta De Santis, Mattia Colucci, Francesco Tamiro, Francesca Sansico, Mattia Miroballo, Emanuele Murgo, Costanzo Padovano, Sam Gusscott, Michele Ciavarella, Elizabeth A. Chavez, Fabrizio Bianchi, Giovanni Rossi, Angelo M. Carella, Christian Steidl, Andrew P. Weng, Vincenzo Giambra
Journal: Blood (2022)

T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of β-catenin in T-ALL, we performed coimmunoprecipitation followed by liquid chromatography-mass spectrometry. Here, we report that a noncanonical functional interaction of β-catenin with the Forkhead box O3 (FOXO3) transcription factor positively regulates LIC-related genes, including the cyclin-dependent kinase 4, which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. In addition, gene expression data at the single-cell level of leukemic cells of primary patients at the time of diagnosis and minimal residual disease (MRD) up to 30 days after the standard treatments reveal that the expression of β-catenin- and FOXO3-dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor ALL. These findings highlight key functional roles for β-catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL.
Dietary iron restriction protects against vaso-occlusion and organ damage in murine sickle cell disease
Authors: Huihui Li, Jacob S. Kazmi, Sungkyun Lee, Dachuan Zhang, Xin Gao, Maria Maryanovich, Lidiane Torres, Divij Verma, Libusha Kelly, Yelena Z. Ginzburg, Paul S. Frenette, Deepa Manwani
Journal: Blood (2022)
Lipoid Pneumonia Associated with Polyethylene Glycol Chronic Aspiration
Authors: Pierre Brancaleone, Quentin Delefortrie, Olivier Descamps, Birgit Weynand, Rita Vanbever, Gautier Detry
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Lipoid Pneumonia Associated with Polyethylene Glycol Chronic Aspiration." American Journal of Respiratory and Critical Care Medicine, 207(8), pp. e71–e72
Effect of High-Intensity Interval Training in Patients With Atrial Fibrillation
Authors: Jennifer L. Reed, Tasuku Terada, Sol Vidal-Almela, Heather E. Tulloch, Matheus Mistura, David H. Birnie, George A. Wells, Girish M. Nair, Harleen Hans, Kimberley L. Way, Daniele Chirico, Carley D. O’Neill, Andrew L. Pipe
Journal: JAMA Network Open (2022)

Importance Patients with atrial fibrillation (AF) experience poor functional capacity and quality of life (QOL). High-intensity interval training (HIIT) has been shown to elicit greater improvements in functional capacity and QOL compared with moderate to vigorous intensity continuous training (MICT) in other cardiovascular populations, yet HIIT remains understudied in AF. Objective To compare the effects of 12 weeks of HIIT and MICT-based cardiovascular rehabilitation (CR) on functional capacity and general QOL in patients with persistent and permanent AF. Disease-specific QOL, resting heart rate (HR), time in AF, and physical activity (PA) levels were also assessed. Design, Setting, and Participants This randomized clinical trial, conducted between November 17, 2015, and February 4, 2020, at a tertiary-care cardiovascular health center in Ottawa, Canada, recruited 94 patients with persistent and permanent AF. Interventions High-intensity interval training (23 minutes: two 8-minute interval training blocks of 30-second work periods at 80%-100% of peak power output interspersed with 30-second recovery) or CR (60 minutes: continuous aerobic conditioning within 67%-95% of peak HR and 12-16 of 20 ratings of perceived exertion) twice weekly for 12 weeks. Main Outcomes and Measures The primary outcomes were changes in functional capacity (6-minute walk test [6MWT] distance) and general QOL (Short Form 36) from baseline to 12 weeks’ follow-up. Secondary outcomes included changes in disease-specific QOL (Atrial Fibrillation Severity Scale), resting HR, time in AF, and PA levels. An intention-to-treat analysis was used to compare changes between groups. Results Of the 94 patients who consented, 86 participated (mean [SD] age, 69 [7] years; 57 [66.3%] men). No significant differences in improvements in 6MWT distance (mean [SD], 21.3 [34.1] vs 13.2 [55.2] m; P = .42) and general QOL (Physical Component Summary, 0.5 [6.1] vs 1.1 [4.9] points; P = .87) between HIIT and CR were observed. No significant differences in improvements in disease-specific QOL (AF symptoms: −1.7 [4.3] vs −1.5 [4] points, P = .59), resting HR (−3.6 [10.6] vs −2.9 [12.4] beats per minute, P = .63), and moderate to vigorous PA levels (37.3 [93.4] vs 14.4 [125.7] min/wk; P = .35) between HIIT and CR were detected. Participants attended a mean (SD) of 18.3 (6.1) (75.1%) HIIT sessions and 20.0 (4.5) (83.4%) CR sessions ( P = .36). Conclusions and Relevance In this randomized clinical trial, twice-weekly 23-minute HIIT was as efficacious as twice-weekly 60-minute CR in improving functional capacity, general and disease-specific QOL, resting HR, and PA levels in patients with persistent and permanent AF. Trial Registration ClinicalTrials.gov Identifier: NCT02602457
Mental Health Morbidities and Time to Cancer Diagnosis Among Adults With Colon Cancer in England
Authors: Sara Benitez Majano, Georgios Lyratzopoulos, Niek J. de Wit, Becky White, Bernard Rachet, Charles Helsper, Juliet Usher-Smith, Cristina Renzi
Journal: JAMA Network Open (2022)

Importance Mental health morbidity (MHM) in patients presenting with possible cancer symptoms may be associated with prediagnostic care and time to cancer diagnosis. Objective To compare the length of intervals to cancer diagnosis by preexisting MHM status in patients who presented with symptoms of as-yet–undiagnosed colon cancer and evaluate their risk of emergency cancer diagnosis. Design, Setting, and Participants This cohort study was conducted using linked primary care data obtained from the population-based Clinical Practice Research Datalink, which includes primary care practices in England, linked to cancer registry and hospital data. Included participants were 3766 patients diagnosed with colon cancer between 2011 and 2015 presenting with cancer-relevant symptoms up to 24 months before their diagnosis. Data analysis was performed in January 2021 to April 2022. Exposures Mental health conditions recorded in primary care before cancer diagnosis, including anxiety, depression, schizophrenia, bipolar disorder, alcohol addiction, anorexia, and bulimia. Main Outcomes and Measures Fast-track (also termed 2–week wait) specialist referral for investigations, time to colonoscopy and cancer diagnosis, and risk of emergency cancer diagnosis. Results Among 3766 patients with colon cancer (median [IQR] age, 75 [65-82] years; 1911 [50.7%] women ), 623 patients [16.5%] had preexisting MHM recorded in primary care the year before cancer diagnosis, including 562 patients (14.9%) with preexisting anxiety or depression (accounting for 90.2% of patients with preexisting MHM) and 61 patients (1.6%) with other MHM; 3143 patients (83.5%) did not have MHM. Patients with MHM had records of red-flag symptoms or signs (ie, rectal bleeding, change in bowel habit, or anemia) in the 24 months before cancer diagnosis in a smaller proportion compared with patients without MHM (308 patients [49.4%] vs 1807 patients [57.5%]; P &amp;amp;lt; .001). Even when red-flag symptoms were recorded, patients with MHM had lower odds of fast-track specialist referral (adjusted odds ratio [OR] = 0.72; 95% CI, 0.55-0.94; P = .01). Among 2115 patients with red-flag symptoms or signs, 308 patients with MHM experienced a more than 2-fold longer median (IQR) time to cancer diagnosis (326 [75-552] days vs 133 [47-422] days) and higher odds of emergency diagnosis (90 patients [29.2%] vs 327 patients [18.1%]; adjusted OR = 1.63; 95% CI, 1.23-2.24; P &amp;amp;lt; .001) compared with 1807 patients without MHM. Conclusions and Relevance This study found that patients with MHM experienced large and prognostically consequential disparities in diagnostic care before a colon cancer diagnosis. These findings suggest that appropriate pathways and follow-up strategies after symptomatic presentation are needed for earlier cancer diagnoses and improved health outcomes in this large patient group.
The Value of Precise and Contemporary Definitions When Categorizing Spinal Injections—Reply
Authors: Thomas R. Radomski, Elijah Z. Lovelace, Carolyn T. Thorpe
Journal: JAMA Internal Medicine (2022)

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Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease
Authors: Kara N. Stevens, Siobhan Creanor, Alison Jeffery, Alan Whone, John Zajicek, Andy Foggo, Ben Jones, Rebecca Chapman, Laura Cocking, Jonny Wilks, Doug Webb, Camille Carroll, Jemma Inches, Donna Underwood, Julie Frost, Ali James, Christine Schofield, Rob James, Clare O’Reilly, Ray Sheridan, Sarah Statton, Anita Goff, Tamlyn Russell, Alison Whitcher, Sarah Craw, Alison Lewis, Rani Sophia, Khaled Amar, Rochelle Hernandez, Alison Pitcher, Samantha Carvey, Ruth Hamlin, Veronica Lyell, Louisa Aubry, Gillian Carey, Jan Coebergh, Idah Mojela, Sophie Molloy, Yolanda Berceruelo Bergaz, Bintou Camera, Philip Campbell, Huw Morris, Tinashe Samakomva, Anette Schrag, Sarah Fuller, Anjum Misbahuddin, Laura Parker, Elisa Visentin, Stephanie Gallehawk, Jacqueline Rudd, Sudhir Singh, Sarsha Wilson, Julie Creven, Yvonne Croucher, Susan Tluk, Paul Watts, Simone Hargreaves, Danielle Johnson, Lucy Worboys, Paul Worth, Judith Brooke, Christopher Kobylecki, Victoria Parker, Linda Johnson, Rosane Joseph, Julie Melville, Jason Raw, Janice Birt, Marianne Hare, Saifuddin Shaik, Jane Alty, Jeremy Cosgrove, David Burn, Angela Green, Ann McNichol, Nicola Pavese, Helen Pilkington, Maria Price, Kathryn Walker, Ray Chaudhuri, Aleksandra Podlewska, Prashanth Reddy, Dhaval Trivedi, Oliver Bandmann, Rosie Clegg, Grace Cole, Anna Emery, Vaclav Dostal, Jodie Graham, Jocelyn Keshet-Price, Godwin Mamutse, Alex Miller-Fik, Alison Wiltshire, Catherine Wright, Kathryn Dixon, Ahmed Abdelhafiz, Joanne Rose
Journal: JAMA Neurology (2022)

Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy.
Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19–14)
Authors: Choong-Kun Lee, Hong Jae Chon, Jaekyung Cheon, Myung Ah Lee, Hyeon-Su Im, Joung-Soon Jang, Min Hwan Kim, Sejung Park, Beodeul Kang, Moonki Hong, Jin Won Kim, Hyung Soon Park, Myoung Joo Kang, Young Nyun Park, Hye Jin Choi
Journal: The Lancet. Gastroenterology & hepatology (2022)
Targeting RAS mutants in malignancies: successes, failures, and reasons for hope
Authors: Hang Yang, Xinyi Zhou, Dongliang Fu, Chenqin Le, Jiafeng Wang, Quan Zhou, Xiangrui Liu, Ying Yuan, Kefeng Ding, Qian Xiao
Journal: Cancer Communications (2022)

RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform (KRAS, HRAS, and NRAS), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS-targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele-specific inhibitors against KRASG12C . Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS-altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele-specific inhibitors, combination therapies, immunotherapies, and metabolism-associated therapies.
NK cells and solid tumors: therapeutic potential and persisting obstacles
Authors: Le Tong, Carlos Jiménez-Cortegana, Apple H.M. Tay, Stina Wickström, Lorenzo Galluzzi, Andreas Lundqvist
Journal: Molecular Cancer (2022)

Abstract Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.
Biomaterial-embedded extracellular vesicles improve recovery of the dysfunctional myocardium
Authors: Chloé Pezzana, Audrey Cras, Fanny Simelière, Rose Guesdon, Manon Desgres, Bruna Lima Correa, Ashley Peuffier, Valérie Bellamy, Sara Gouarderes, Antonio Alberdi, Marie-Cécile Perier, Laetitia Pidial, Florence Agnely, Amélie Bochot, Albert Hagège, Jean-Sébastien Silvestre, Philippe Menasché
Journal: Biomaterials (2022)
Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome
Authors: Trisha Singh, Shruti Joshi, Lucy E. Kershaw, Andy H. Baker, Gerry P. McCann, Dana K. Dawson, Marc R. Dweck, Scott I. Semple, David E. Newby
Journal: Circulation (2022)

Takotsubo syndrome is an acute cardiac emergency characterized by transient left ventricular systolic dysfunction typically following a stressful event. Despite its rapidly rising incidence, its pathophysiology remains poorly understood. Takotsubo syndrome may pass unrecognized, especially if timely diagnostic imaging is not performed. Defective myocardial calcium homeostasis is a central cause of contractile dysfunction and has not been explored in takotsubo syndrome. We aimed to investigate myocardial calcium handling using manganese-enhanced magnetic resonance imaging during the acute and recovery phases of takotsubo syndrome.
Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis
Authors: Mingjie Zheng, Rich G. Li, Jia Song, Xiaolei Zhao, Li Tang, Shannon Erhardt, Wen Chen, Bao H. Nguyen, Xiao Li, Min Li, Jianxin Wang, Sylvia M. Evans, Vincent M. Christoffels, Na Li, Jun Wang
Journal: Circulation (2022)

The sinoatrial node (SAN) functions as the pacemaker of the heart, initiating rhythmic heartbeats. Despite its importance, the SAN is one of the most poorly understood cardiac entities because of its small size and complex composition and function. The Hippo signaling pathway is a molecular signaling pathway fundamental to heart development and regeneration. Although abnormalities of the Hippo pathway are associated with cardiac arrhythmias in human patients, the role of this pathway in the SAN is unknown.We investigated key regulators of the Hippo pathway in SAN pacemaker cells by conditionally inactivating the Hippo signaling kinases Lats1 and Lats2 using the tamoxifen-inducible, cardiac conduction system-specific Cre driver Hcn4CreERT2 with Lats1 and Lats2 conditional knockout alleles. In addition, the Hippo-signaling effectors Yap and Taz were conditionally inactivated in the SAN. To determine the function of Hippo signaling in the SAN and other cardiac conduction system components, we conducted a series of physiological and molecular experiments, including telemetry ECG recording, echocardiography, Masson Trichrome staining, calcium imaging, immunostaining, RNAscope, cleavage under targets and tagmentation sequencing using antibodies against Yap1 or H3K4me3, quantitative real-time polymerase chain reaction, and Western blotting. We also performed comprehensive bioinformatics analyses of various datasets.We found that Lats1/2 inactivation caused severe sinus node dysfunction. Compared with the controls, Lats1/2 conditional knockout mutants exhibited dysregulated calcium handling and increased fibrosis in the SAN, indicating that Lats1/2 function through both cell-autonomous and non-cell-autonomous mechanisms. It is notable that the Lats1/2 conditional knockout phenotype was rescued by genetic deletion of Yap and Taz in the cardiac conduction system. These rescued mice had normal sinus rhythm and reduced fibrosis of the SAN, indicating that Lats1/2 function through Yap and Taz. Cleavage Under Targets and Tagmentation sequencing data showed that Yap potentially regulates genes critical for calcium homeostasis such as Ryr2 and genes encoding paracrine factors important in intercellular communication and fibrosis induction such as Tgfb1 and Tgfb3. Consistent with this, Lats1/2 conditional knockout mutants had decreased Ryr2 expression and increased Tgfb1 and Tgfb3 expression compared with control mice.We reveal, for the first time to our knowledge, that the canonical Hippo-Yap pathway plays a pivotal role in maintaining SAN homeostasis.